卡培他滨有关物质的制备

Preparation of the related substances of capecitabine

目的加强对抗肿瘤药物卡培他滨原料药的质量控制,进行强制降解试验,研究产生的降解产物,同时合成欧洲药典收录的7个有关物质A~G,并确证其结构。方法对卡培他滨原料药分别进行热破坏、酸降解、碱降解、氧化降解,分离降解产物,并进行结构确证和纯度测定。以1,2,3-三-O-乙酰基-5-脱氧-β-D-核糖(8)为起始原料,经Silyl-Hibert-Johnson反应得到杂质B和C;杂质C进一步水解得到杂质A,接入不同的酯基得到杂质D、E、G;杂质G经水解、碳酸酯缩合得到杂质F。结果与结论强制降解试验得到7个降解产物,合成7个药典收录杂质,共计得到12个不同类型的有关物质,结构经^(1)H-NMR、LC-MS确证,纯度均大于95%,可作为卡培他滨原料药质量控制的杂质对照品。

In order to perform the quality control of anti-tumour drug capecitabine,the forced degradation tests were carried out,including heat,hydrolysis and oxidation.The degradation products were separated and confirmed.Meanwhile,the impurities collected by European Pharmacopoeia were synthesized.Impurities B and C were prepared with 1,2,3-tri-O-acetyl-5-deoxy-β-D-ribofuranose(8)by Silyl-Hibert-Johnson reaction.Hydrolyzation of impurity C gave impurity A.Impurities D,E and G were obtained by introduction of different esters.Impurity F was obtained by hydrolyzation and carbonate condensation of impurity G.Therefore,totally 12 different related substances were prepared(>95%purity),and their structures were confirmed by^(1)H-NMR and LC-MS,which can be used as references for the quality control of capecitabine.